Abstract
A decade of research has demonstrated the explanatory potential of interplay between genetic variants and environmental factors in the development of common mental disorders. Initial findings have undergone tests of replicability and specificity. Some gene–environment interactions have been confirmed, some have not replicated and yet other turned out to be more specific than initially thought. Specific and complementary roles of genetic factors have been delineated: a common functional length polymorphism in the serotonin transporter gene (5-HTTLPR) moderated the effect of childhood maltreatment on chronic depression in adulthood, but did not substantially influence the effects of adult stressful life events on the onset of new depressive episodes; in contrast, a common functional polymorphism in the brain-derived neurotrophic factor gene (BDNF) moderated the effect of stressful life events in adulthood in triggering new depressive episodes, but did not influence the effects of childhood maltreatment. Molecular mechanisms underlying gene–environment interactions are being uncovered, including DNA methylation and other epigenetic modifications. New gene–environment interactions continue to be reported, still largely from hypothesis-driven research. Statistical and biological prioritization strategies are proposed to facilitate a systematic discovery of novel gene–environment interactions in genome-wide analyses.
Similar content being viewed by others
Notes
This induced relationship is distinct from a gene–environment correlation (rGE) which denotes a true association between a genotype and exposure in the population (see reference [3]).
References
Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301:386–389
Battaglia M (2013) Gene–environment interaction in panic disorder and posttraumatic stress disorder. Can J Psychiatry 58:69–75
Jaffee SR, Price TS (2007) Gene–environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry 12:432–442
Power RA, Kyaga S, Uher R, MacCabe JH, Langstrom N, Landen M, McGuffin P, Lewis CM, Lichtenstein P, Svensson AC (2013) Fecundity of patients with schizophrenia, autism, bipolar disorder, depression, anorexia nervosa, or substance abuse vs their unaffected siblings. JAMA Psychiatry 70:22–30
Uher R (2009) The role of genetic variation in the causation of mental illness: an evolution-informed framework. Mol Psychiatry 14:1072–1082
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45:984–994
Uher R (2013) Genomics and the classification of mental illness: focus on broader categories. Genome Med 5:97
Uher R (2008) The implications of gene–environment interactions in depression: will cause inform cure? Mol Psychiatry 13:1070–1078
Kendler KS, Kessler RC, Walters EE, MacLean C, Neale MC, Heath AC, Eaves LJ (1995) Stressful life events, genetic liability, and onset of an episode of major depression in women. Am J Psychiatry 152:833–842
Wicks S, Hjern A, Dalman C (2010) Social risk or genetic liability for psychosis? A study of children born in Sweden and reared by adoptive parents. Am J Psychiatry 167:1240–1246
Psychiatric Genetic Consortium (2013) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18:497–511
Uher R (2008) Forum: the case for gene–environment interactions in psychiatry. Curr Opin Psychiatry 21:318–321
Grizenko N, Fortier ME, Zadorozny C, Thakur G, Schmitz N, Duval R, Joober R (2012) Maternal stress during pregnancy, ADHD symptomatology in children and genotype: gene–environment interaction. J Can Acad Child Adolesc Psychiatry 21:9–15
van der Zwaluw CS, Otten R, Kleinjan M, Engels RC (2013) Different trajectories of adolescent alcohol use: testing gene–environment interactions. Alcohol Clin Exp Res
Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE (2010) Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 167:509–527
Byrd AL, Manuck SB (2013) MAOA, childhood maltreatment, and antisocial behavior: meta-analysis of a gene–environment interaction. Biol Psychiatry
Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297:851–854
Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, Tang Y, Gillespie CF, Heim CM, Nemeroff CB, Schwartz AC, Cubells JF, Ressler KJ (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299:1291–1305
Bradley RG, Binder EB, Epstein MP, Tang Y, Nair HP, Liu W, Gillespie CF, Berg T, Evces M, Newport DJ, Stowe ZN, Heim CM, Nemeroff CB, Schwartz A, Cubells JF, Ressler KJ (2008) Influence of child abuse on adult depression: moderation by the corticotropin-releasing hormone receptor gene. Arch Gen Psychiatry 65:190–200
Polanczyk G, Caspi A, Williams B, Price TS, Danese A, Sugden K, Uher R, Poulton R, Moffitt TE (2009) Protective effect of CRHR1 gene variants on the development of adult depression following childhood maltreatment: replication and extension. Arch Gen Psychiatry 66:978–985
Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Farrer LA, Gelernter J (2010) Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder. Neuropsychopharmacology 35:1684–1692
Martel MM, Nikolas M, Jernigan K, Friderici K, Waldman I, Nigg JT (2010) The dopamine receptor D4 gene (DRD4) moderates family environmental effects on ADHD. J Abnorm Child Psychol 39(1):1–10
Sheese BE, Voelker PM, Rothbart MK, Posner MI (2007) Parenting quality interacts with genetic variation in dopamine receptor D4 to influence temperament in early childhood. Dev Psychopathol 19:1039–1046
Kim-Cohen J, Caspi A, Taylor A, Williams B, Newcombe R, Craig IW, Moffitt TE (2006) MAOA, maltreatment, and gene–environment interaction predicting children’s mental health: new evidence and a meta-analysis. Mol Psychiatry 11:903–913
Taylor A, Kim-Cohen J (2007) Meta-analysis of gene–environment interactions in developmental psychopathology. Dev Psychopathol 19:1029–1037
Chang SC, Xie P, Anton RF, De V I, Farrer LA, Kranzler HR, Oslin D, Purcell SM, Roberts AL, Smoller JW, Uddin M, Gelernter J, Koenen KC (2012) No association between ADCYAP1R1 and post-traumatic stress disorder in two independent samples. Mol Psychiatry 17:239–241
Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V (2011) Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Nature 470:492–497
Brookes KJ, Mill J, Guindalini C, Curran S, Xu X, Knight J, Chen CK, Huang YS, Sethna V, Taylor E, Chen W, Breen G, Asherson P (2006) A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry 63:74–81
Kahn RS, Khoury J, Nichols WC, Lanphear BP (2003) Role of dopamine transporter genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional behaviors. J Pediatr 143:104–110
Kieling C, Hutz MH, Genro JP, Polanczyk GV, Anselmi L, Camey S, Hallal PC, Barros FC, Victora CG, Menezes AM, Rohde LA (2013) Gene–environment interaction in externalizing problems among adolescents: evidence from the Pelotas 1993 Birth Cohort Study. J Child Psychol Psychiatry 54:298–304
Karg K, Burmeister M, Shedden K, Sen S (2011) The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation. Arch Gen Psychiatry 68:444–454
Tiemeier H, Velders FP, Szekely E, Roza SJ, Dieleman G, Jaddoe VW, Uitterlinden AG, White TJ, Bakermans-Kranenburg MJ, Hofman A, van Ijzendoorn MH, Hudziak JJ, Verhulst FC (2012) The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward. J Am Acad Child Adolesc Psychiatry 51:1119–1135
Uher R, McGuffin P (2008) The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis. Mol Psychiatry 13:131–146
Uher R, McGuffin P (2010) The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update. Mol Psychiatry 15:18–22
Brown GW, Harris TO (2008) Depression and the serotonin transporter 5-HTTLPR polymorphism: a review and a hypothesis concerning gene–environment interaction. J Affect Disord 111:1–12
Uher R, Caspi A, Houts R, Sugden K, Williams B, Poulton R, Moffitt TE (2011) Serotonin transporter gene moderates childhood maltreatment’s effects on persistent but not single-episode depression: replications and implications for resolving inconsistent results. J Affect Disord 135:56–65
Brown GW, Ban M, Craig TK, Harris TO, Herbert J, Uher R (2013) Serotonin transporter length polymorphism, childhood maltreatment, and chronic depression: a specific gene–environment interaction. Depress Anxiety 30:5–13
Fisher HL, Cohen-Woods S, Hosang GM, Uher R, Powell-Smith G, Keers R, Tropeano M, Korszun A, Jones L, Jones I, Owen M, Craddock N, Craig IW, Farmer AE, McGuffin P (2012) Stressful life events and the serotonin transporter gene (5-HTT) in recurrent clinical depression. J Affect Disord 136:189–193
Fisher HL, Cohen-Woods S, Hosang GM, Korszun A, Owen M, Craddock N, Craig IW, Farmer AE, McGuffin P, Uher R (2013) Interaction between specific forms of childhood maltreatment and the serotonin transporter gene (5-HTT) in recurrent depressive disorder. J Affect Disord 145:136–141
Brown GW, Harris TO (1978) Social origins of depression. A study of psychiatric disorder in women. Routledge, London
Matrisciano F, Modafferi AM, Togna GI, Barone Y, Pinna G, Nicoletti F, Scaccianoce S (2010) Repeated anabolic androgenic steroid treatment causes antidepressant-reversible alterations of the hypothalamic-pituitary-adrenal axis, BDNF levels and behavior. Neuropharmacology 58:1078–1084
Terracciano A, Lobina M, Piras MG, Mulas A, Cannas A, Meirelles O, Sutin AR, Zonderman AB, Uda M, Crisponi L, Schlessinger D (2011) Neuroticism, depressive symptoms, and serum BDNF. Psychosom Med 73:638–642
Brown GW, Craig TKJ, Harris TO, Herbert J, Hodgson K, Tansey KE, Uher R (2014) A functional polymorphism in the brain-derived neurotrophic factor gene interacts with stressful life events but not childhood maltreatment in the etiology of depression. Depress Anxiety
Hosang GM, Shiles C, Tansey KE, McGuffin P, Uher R (2013) Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med
Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (2006) Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nat Neurosci 9:519–525
Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM, Pace TW, Mercer KB, Mayberg HS, Bradley B, Nemeroff CB, Holsboer F, Heim CM, Ressler KJ, Rein T, Binder EB (2013) Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nat Neurosci 16:33–41
Melas PA, Wei Y, Wong CC, Sjoholm LK, Aberg E, Mill J, Schalling M, Forsell Y, Lavebratt C (2013) Genetic and epigenetic associations of MAOA and NR3C1 with depression and childhood adversities. Int J Neuropsychopharmacol 16:1513–1528
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonte B, Szyf M, Turecki G, Meaney MJ (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12:342–348
Perroud N, Dayer A, Piguet C, Nallet A, Favre S, Malafosse A, Aubry JM (2014) Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder. Br J Psychiatry 204
Turecki G (2013) The epigenetic basis of behavioral phenotypes: is there reason for continued optimism? Depress Anxiety
Perroud N, Paoloni-Giacobino A, Prada P, Olie E, Salzmann A, Nicastro R, Guillaume S, Mouthon D, Stouder C, Dieben K, Huguelet P, Courtet P, Malafosse A (2011) Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma. Transl Psychiatry 1:e59
Uher R, Weaver IC (2014) Epigenetic traces of childhood maltreatment in peripheral blood: a new strategy to explore gene–environment interactions. Br J Psychiatry 204:3–4
Bet PM, Penninx BW, Bochdanovits Z, Uitterlinden AG, Beekman AT, van Schoor NM, Deeg DJ, Hoogendijk WJ (2009) Glucocorticoid receptor gene polymorphisms and childhood adversity are associated with depression: new evidence for a gene–environment interaction. Am J Med Genet B Neuropsychiatr Genet 150B:660–669
Klengel T, Binder EB (2013) Gene–environment interactions in major depressive disorder. Can J Psychiatry 58:76–83
Cornelis MC, Tchetgen EJ, Liang L, Qi L, Chatterjee N, Hu FB, Kraft P (2012) Gene–environment interactions in genome-wide association studies: a comparative study of tests applied to empirical studies of type 2 diabetes. Am J Epidemiol 175:191–202
Aschard H, Lutz S, Maus B, Duell EJ, Fingerlin TE, Chatterjee N, Kraft P, Van SK (2012) Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Hum Genet 131:1591–1613
Monroe SM, Reid MW (2008) Gene–environment interactions in depression research: genetic polymorphisms and life-stress polyprocedures. Psychol Sci 19:947–956
Galea S (2011) The urban brain: new directions in research exploring the relation between cities and mood-anxiety disorders. Depress Anxiety 28:857–862
Perren S, Dooley J, Shaw T, Cross D (2010) Bullying in school and cyberspace: associations with depressive symptoms in Swiss and Australian adolescents. Child Adolesc Psychiatry Ment Health 4:28
Finkelhor D, Shattuck A, Turner H, Hamby S (2013) Improving the adverse childhood experiences study scale. JAMA Pediatr 167:70–75
McClelland GH, Judd CM (1993) Statistical difficulties of detecting interactions and moderator effects. Psychol Bull 114:376–390
Uher R (2008) Gene–environment interaction: overcoming methodological challenges. Novartis Found Symp 293:13–26
Borglum AD, Demontis D, Grove J, Pallesen J, Hollegaard MV, Pedersen CB, Hedemand A, Mattheisen M, Uitterlinden A, Nyegaard M, Orntoft T, Wiuf C, Didriksen M, Nordentoft M, Nothen MM, Rietschel M, Ophoff RA, Cichon S, Yolken RH, Hougaard DM, Mortensen PB, Mors O (2013) Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci. Mol Psychiatry
Odgers CL, Caspi A, Bates CJ, Sampson RJ, Moffitt TE (2012) Systematic social observation of children’s neighborhoods using Google Street View: a reliable and cost-effective method. J Child Psychol Psychiatry 53:1009–1017
Gauderman WJ, Zhang P, Morrison JL, Lewinger JP (2013) Finding novel genes by testing G×E interactions in a genome-wide association study. Genet Epidemiol 37:603–613
Murcray CE, Lewinger JP, Gauderman WJ (2009) Gene–environment interaction in genome-wide association studies. Am J Epidemiol 169:219–226
Power RA, Cohen-Woods S, Ng MY, Butler AW, Craddock N, Korszun A, Jones L, Jones I, Gill M, Rice JP, Maier W, Zobel A, Mors O, Placentino A, Rietschel M, Aitchison KJ, Tozzi F, Muglia P, Breen G, Farmer AE, McGuffin P, Lewis CM, Uher R (2013) Genome-wide association analysis accounting for environmental factors through propensity-score matching: application to stressful live events in major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 162B:521–529
Rothman KJ, Greenland S, Lash TL (2008) Modern epidemiology. Wolter Kluwer Health; Lippincott Williams and Wilkins, Philadelphia
Ottman R (1996) Gene–environment interaction: definitions and study designs. Prev Med 25:764–770
Amstadter AB, Koenen KC, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, Gelernter J (2009) Variant in RGS2 moderates posttraumatic stress symptoms following potentially traumatic event exposure. J Anxiety Disord 23:369–373
Schellekens AF, Franke B, Ellenbroek B, Cools A, de Jong CA, Buitelaar JK, Verkes RJ (2013) COMT Val158Met modulates the effect of childhood adverse experiences on the risk of alcohol dependence. Addict Biol 18:344–356
Stevens SE, Kumsta R, Kreppner JM, Brookes KJ, Rutter M, Sonuga-Barke EJ (2009) Dopamine transporter gene polymorphism moderates the effects of severe deprivation on ADHD symptoms: developmental continuities in gene–environment interplay. Am J Med Genet B Neuropsychiatr Genet 150B:753–761
van der Zwaluw CS, Engels RC, Vermulst AA, Franke B, Buitelaar J, Verkes RJ, Scholte RH (2010) Interaction between dopamine D2 receptor genotype and parental rule-setting in adolescent alcohol use: evidence for a gene–parenting interaction. Mol Psychiatry 15:727–735
Jokela M, Keltikangas-Jarvinen L, Kivimaki M, Puttonen S, Elovainio M, Rontu R, Lehtimaki T (2007) Serotonin receptor 2A gene and the influence of childhood maternal nurturance on adulthood depressive symptoms. Arch Gen Psychiatry 64:356–360
Dammann G, Teschler S, Haag T, Altmuller F, Tuczek F, Dammann RH (2011) Increased DNA methylation of neuropsychiatric genes occurs in borderline personality disorder. Epigenetics 6:1454–1462
Docherty SJ, Davis OS, Haworth CM, Plomin R, D’Souza U, Mill J (2012) A genetic association study of DNA methylation levels in the DRD4 gene region finds associations with nearby SNPs. Behav Brain Funct 8:31
Keller S, Sarchiapone M, Zarrilli F, Videtic A, Ferraro A, Carli V, Sacchetti S, Lembo F, Angiolillo A, Jovanovic N, Pisanti F, Tomaiuolo R, Monticelli A, Balazic J, Roy A, Marusic A, Cocozza S, Fusco A, Bruni CB, Castaldo G, Chiariotti L (2010) Increased BDNF promoter methylation in the Wernicke area of suicide subjects. Arch Gen Psychiatry 67:258–267
Koenen KC, Uddin M, Chang SC, Aiello AE, Wildman DE, Goldmann E, Galea S (2011) SLC6A4 methylation modifies the effect of the number of traumatic events on risk for posttraumatic stress disorder. Depress Anxiety 28:639–647
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM (2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3:97–106
Oertel BG, Doehring A, Roskam B, Kettner M, Hackmann N, Ferreiros N, Schmidt PH, Lotsch J (2012) Genetic–epigenetic interaction modulates mu-opioid receptor regulation. Hum Mol Genet 21:4751–4760
Ouellet-Morin I, Wong CC, Danese A, Pariante CM, Papadopoulos AS, Mill J, Arseneault L (2013) Increased serotonin transporter gene (SERT) DNA methylation is associated with bullying victimization and blunted cortisol response to stress in childhood: a longitudinal study of discordant monozygotic twins. Psychol Med 43:1813–1823
Tyrka AR, Price LH, Marsit C, Walters OC, Carpenter LL (2012) Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults. PLoS ONE 7:e30148
Aguilera M, Arias B, Wichers M, Barrantes-Vidal N, Moya J, Villa H, van OJ, Ibanez MI, Ruiperez MA, Ortet G, Fananas L (2009) Early adversity and 5-HTT/BDNF genes: new evidence of gene-environment interactions on depressive symptoms in a general population. Psychol Med 39:1425–1432
Cicchetti D, Rogosch FA, Sturge-Apple ML (2007) Interactions of child maltreatment and serotonin transporter and monoamine oxidase A polymorphisms: depressive symptomatology among adolescents from low socioeconomic status backgrounds. Dev Psychopathol 19:1161–1180
Koenen KC, Amstadter AB, Ruggiero KJ, Acierno R, Galea S, Kilpatrick DG, Gelernter J (2009) RGS2 and generalized anxiety disorder in an epidemiologic sample of hurricane-exposed adults. Depress Anxiety 26:309–315
Langley K, Turic D, Rice F, Holmans P, van den Bree MB, Craddock N, Kent L, Owen MJ, O'Donovan MC, Thapar A (2008) Testing for gene x environment interaction effects in attention deficit hyperactivity disorder and associated antisocial behavior. Am J Med Genet B Neuropsychiatr Genet 147B:49–53
Acknowledgments
Dr. Uher is supported by the Canada Research Chairs program (http://www.chairs-chaires.gc.ca/), the Canadian Institutes of Health Research, the Nova Scotia Health Research Foundation and the European Commission Innovative Medicine Initiative Joint Undertaking (#115008).
Conflict of interest
Dr. Uher has received no personal income from pharmaceutical or biotech industry and holds no equity in companies active in medicine, pharmaceuticals or biotechnology. Dr. Uher consults for the World Health Organization. Dr Uher has collaborated with a number of pharmaceutical companies as part of the European Union Innovative Medicine Initiative funded NEWMEDS project.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Uher, R. Gene–environment interactions in common mental disorders: an update and strategy for a genome-wide search. Soc Psychiatry Psychiatr Epidemiol 49, 3–14 (2014). https://doi.org/10.1007/s00127-013-0801-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00127-013-0801-0